This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and hypothesis: Vascular disease is the major risk factor responsible for myocardial infarction in hypertensive patients. However, the molecular mechanisms that mediate vascular disease in hypertension are poorly understood. Even with the most aggressive treatment available, there is an enormous amount of residual vascular risk responsible for a large number of deaths in the UNITED STATES. Our central hypothesis is that elevated oxidative stress activates NFKB pathway, which leads to avb3-integrin shedding responsible for the increased TGFb1 bio-activity and subsequently the induction of structural wall remodeling in Ang-II-dependent hypertensive mice. We will use mesenteric resistance arteries (MRA) because they are good model reflecting changes in vessels, representative of microvessels and responsible for more than 30% blood pressure control. We have two Specific Aims under this proposal: Overall, our Specific Aim 1 is focused on the role of oxidative stress and NFKB pathways responsible for the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from Ang-II-dependent hypertensive mice. Subaim 1a: treatment of Ang-II-dependent hypertensive mice apocynin or mitoquinone (MitoQ: is a mitochondria-targeted antioxidant that selectively blocks mitochondrial oxidative stress)", and the use of mice that over-express mitochondrial MnSOD infused with Ang-II to reduce NFKB pathway activation and translocation, avb3-integrin shedding, TGFb1 bioactivity, eutrophic remodeling, collagen type 1 content, and stiffness of MRA from Ang-II-dependent hypertensive mice; Subaim 1b: local down regulation of NFKB pathway by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated IKB or p50/p65 NFKB subunits-siRNA delivery potentiates or reduces, respectively, avb3-integrin shedding, TGFb1 expression, collagen type 1 content, stiffness and eutrophic remodeling induction; Overall, our Specific Aim 2 is directed to determine the role of avb3-integrin shedding and TGFb1 bio-activity on collagen type 1 content, stiffness, and eutrophic remodeling induction in MRA from Ang-II-dependent hypertensive mice. To accomplish this aim, we will ascertain if: 2a: local down regulation of avb3-integrin by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated avb3-integrin-siRNA delivery and the use of pharmacological inhibition of avb3-integrin reduce the increased TGFb1 bioactivity, collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from; 2b: local down regulation of TGFb1 by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated TGFb1-siRNA delivery, and the use of mice overexpressing dominant negative TGFb1 receptor infused with ANG II reverse the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA.